Cocaine use reduction with buprenorphine (CURB): rationale, design, and methodology.
Effective medications to treat cocaine dependence have not been identified. Recent pharmacotherapy trials demonstrate the potential efficacy of buprenorphine (BUP) (alone or with naltrexone) for reducing cocaine use. The National Institute on Drug Abuse Clinical Trials Network (CTN) launched the Cocaine Use Reduction with Buprenorphine (CURB) investigation to examine the safety and efficacy of sublingual BUP (as Suboxone®) in the presence of extended-release injectable naltrexone (XR-NTX, as Vivitrol®) for the treatment of cocaine dependence. This paper describes the design and rationale for this study. This multi-site, double-blind, placebo-controlled study will randomize 300 participants across 11 sites. Participants must meet the DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. Participants are inducted onto XR-NTX after self-reporting at least 7 days of abstinence from opioids and tolerating a naloxone challenge followed by oral naltrexone and are then randomly assigned to one of three medication conditions (4 mg BUP, 16 mg BUP, or placebo) for 8 weeks. Participants receive a second injection of XR-NTX 4 weeks after the initial injection, and follow-up visits are scheduled at 1 and 3 months post-treatment. Participants receive weekly cognitive behavioral therapy (CBT). Recruitment commenced in September, 2011. Enrollment, active medication, and follow-up phases are ongoing, and recruitment is exceeding targeted enrollment rates. This research using 2 medications will demonstrate whether BUP, administered in the presence of XR-NTX, reduces cocaine use in adults with cocaine dependence and opioid use disorders and will demonstrate if XR-NTX prevents development of physiologic dependence on BUP.


2020 consensus guideline for optimal approach to the diagnosis and treatment of HER2-positive breast cancer in Bosnia and Herzegovina.
The HERe2Cure project, which involved a group of breast cancer experts, members of multidisciplinary tumor boards from healthcare institutions in Bosnia and Herzegovina, was initiated with the aim of defining an optimal approach to the diagnosis and treatment of HER2 positive breast cancer. After individual multidisciplinary consensus meetings were held in all oncology centers in Bosnia and Herzegovina, a final consensus meeting was held in order to reconcile the final conclusions discussed in individual meetings. Guidelines were adopted by consensus, based on the presentations and suggestions of experts, which were first discussed in a panel discussion and then agreed electronically between all the authors mentioned. The conclusions of the panel discussion represent the consensus of experts in the field of breast cancer diagnosis and treatment in Bosnia and Herzegovina. The objectives of the guidelines include the standardization, harmonization and optimization of the procedures for the diagnosis, treatment and monitoring of patients with HER2-positive breast cancer, all of which should lead to an improvement in the quality of health care of mentioned patients. The initial treatment plan for patients with HER2-positive breast cancer must be made by a multidisciplinary tumor board comprised of at least: a medical oncologist, a pathologist, a radiologist, a surgeon, and a radiation oncologist/radiotherapist.


Carbon Dioxide Embolism Associated With Transanal Total Mesorectal Excision Surgery: A Report From the International Registries.
Carbon dioxide embolus has been reported as a rare but clinically important risk associated with transanal total mesorectal excision surgery. To date, there exists limited data describing the incidence, risk factors, and management of carbon dioxide embolus in transanal total mesorectal excision. This study aimed to obtain data from the transanal total mesorectal excision registries to identify trends and potential risk factors for carbon dioxide embolus specific to this surgical technique. Contributors to both the LOREC and OSTRiCh transanal total mesorectal excision registries were invited to report their incidence of carbon dioxide embolus. Case report forms were collected detailing the patient-specific and technical factors of each event. The study was conducted at the collaborating centers from the international transanal total mesorectal excision registries. Characteristics and outcomes of patients with carbon dioxide embolus associated with transanal mesorectal excision were measured. Twenty-five cases were reported. The incidence of carbon dioxide embolus during transanal total mesorectal excision is estimated to be ≈0.4% (25/6375 cases). A fall in end tidal carbon dioxide was noted as the initial feature in 22 cases, with 13 (52%) developing signs of hemodynamic compromise. All of the events occurred in the transanal component of dissection, with mean (range) insufflation pressures of 15 mm Hg (12-20 mm Hg). Patients were predominantly (68%) in a Trendelenburg position, between 30° and 45°. Venous bleeding was reported in 20 cases at the time of carbon dioxide embolus, with periprostatic veins documented as the most common site (40%). After carbon dioxide embolus, 84% of cases were completed after hemodynamic stabilization. Two patients required cardiopulmonary resuscitation because of cardiovascular collapse. There were no deaths. This is a retrospective study surveying reported outcomes by surgeons and anesthetists. Surgeons undertaking transanal total mesorectal excision must be aware of the possibility of carbon dioxide embolus and its potential risk factors, including venous bleeding (wrong plane surgery), high insufflation pressures, and patient positioning. Prompt recognition and management can limit the clinical impact of such events. See Video Abstract at http://links.lww.com/DCR/A961.


Reduction of global interference of scalp-hemodynamics in functional near-infrared spectroscopy using short distance probes.
Functional near-infrared spectroscopy (fNIRS) is used to measure cerebral activity because it is simple and portable. However, scalp-hemodynamics often contaminates fNIRS signals, leading to detection of cortical activity in regions that are actually inactive. Methods for removing these artifacts using standard source-detector distance channels (Long-channel) tend to over-estimate the artifacts, while methods using additional short source-detector distance channels (Short-channel) require numerous probes to cover broad cortical areas, which leads to a high cost and prolonged experimental time. Here, we propose a new method that effectively combines the existing techniques, preserving the accuracy of estimating cerebral activity and avoiding the disadvantages inherent when applying the techniques individually. Our new method accomplishes this by estimating a global scalp-hemodynamic component from a small number of Short-channels, and removing its influence from the Long-channels using a general linear model (GLM). To demonstrate the feasibility of this method, we collected fNIRS and functional magnetic resonance imaging (fMRI) measurements during a motor task. First, we measured changes in oxygenated hemoglobin concentration (∆Oxy-Hb) from 18 Short-channels placed over motor-related areas, and confirmed that the majority of scalp-hemodynamics was globally consistent and could be estimated from as few as four Short-channels using principal component analysis. We then measured ∆Oxy-Hb from 4 Short- and 43 Long-channels. The GLM identified cerebral activity comparable to that measured separately by fMRI, even when scalp-hemodynamics exhibited substantial task-related modulation. These results suggest that combining measurements from four Short-channels with a GLM provides robust estimation of cerebral activity at a low cost.


Framework for 3D histologic reconstruction and fusion with in vivo MRI: Preliminary results of characterizing pulmonary inflammation in a mouse model.
Pulmonary inflammation is associated with a variety of diseases. Assessing pulmonary inflammation on in vivo imaging may facilitate the early detection and treatment of lung diseases. Although routinely used in thoracic imaging, computed tomography has thus far not been compellingly shown to characterize inflammation in vivo. Alternatively, magnetic resonance imaging (MRI) is a nonionizing radiation technique to better visualize and characterize pulmonary tissue. Prior to routine adoption of MRI for early characterization of inflammation in humans, a rigorous and quantitative characterization of the utility of MRI to identify inflammation is required. Such characterization may be achieved by considering ex vivo histology as the ground truth, since it enables the definitive spatial assessment of inflammation. In this study, the authors introduce a novel framework to integrate 2D histology, ex vivo and in vivo imaging to enable the mapping of the extent of disease from ex vivo histology onto in vivo imaging, with the goal of facilitating computerized feature analysis and interrogation of disease appearance on in vivo imaging. The authors' framework was evaluated in a preclinical preliminary study aimed to identify computer extracted features on in vivo MRI associated with chronic pulmonary inflammation. The authors' image analytics framework first involves reconstructing the histologic volume in 3D from individual histology slices. Second, the authors map the disease ground truth onto in vivo MRI via coregistration with 3D histology using the ex vivo lung MRI as a conduit. Finally, computerized feature analysis of the disease extent is performed to identify candidate in vivo imaging signatures of disease presence and extent. The authors evaluated the framework by assessing the quality of the 3D histology reconstruction and the histology-MRI fusion, in the context of an initial use case involving characterization of chronic inflammation in a mouse model. The authors' evaluation considered three mice, two with an inflammation phenotype and one control. The authors' iterative 3D histology reconstruction yielded a 70.1% ± 2.7% overlap with the ex vivo MRI volume. Across a total of 17 anatomic landmarks manually delineated at the division of airways, the target registration error between the ex vivo MRI and 3D histology reconstruction was 0.85 ± 0.44 mm, suggesting that a good alignment of the ex vivo 3D histology and ex vivo MRI had been achieved. The 3D histology-in vivo MRI coregistered volumes resulted in an overlap of 73.7% ± 0.9%. Preliminary computerized feature analysis was performed on an additional four control mice, for a total of seven mice considered in this study. Gabor texture filters appeared to best capture differences between the inflamed and noninflamed regions on MRI. The authors' 3D histology reconstruction and multimodal registration framework were successfully employed to reconstruct the histology volume of the lung and fuse it with in vivo MRI to create a ground truth map for inflammation on in vivo MRI. The analytic platform presented here lays the framework for a rigorous validation of the identified imaging features for chronic lung inflammation on MRI in a large prospective cohort.


The Effects of a Lifestyle Intervention Supported by the InterWalk Smartphone App on Increasing Physical Activity Among Persons With Type 2 Diabetes: Parallel-Group, Randomized Trial.
Effective and sustainable implementation of physical activity (PA) in type 2 diabetes (T2D) health care has in general not been successful. Efficacious and contemporary approaches to support PA adherence and adoption are required. The primary objective of this study was to investigate the effectiveness of including an app-based (InterWalk) approach in municipality-based rehabilitation to increase moderate-and-vigorous PA (MVPA) across 52 weeks compared with standard care among individuals with T2D. The study was designed as a parallel-group, randomized trial with 52 weeks' intervention and subsequent follow-up for effectiveness (52 weeks from baseline). Participants were recruited between January 2015 and December 2016 and randomly allocated (2:1) into 12 weeks of (1) standard care + InterWalk app-based interval walking training (IWT; IWT group; n=140), or (2) standard care + the standard exercise program (StC group; n=74). Following 12 weeks, the IWT group was encouraged to maintain InterWalk app-based IWT (3 times per week for 30-60 minutes) and the StC group was encouraged to maintain exercise without structured support. Moreover, half of the IWT group (IWTsupport group, n=54) received additional motivational support following the 12-week program until 52-week follow-up. The primary outcome was change in objectively measured MVPA time (minutes/day) from baseline to 52-week follow-up. Key secondary outcomes included changes in self-rated physical and mental health-related quality of life (HRQoL), physical fitness, weight, and waist circumference. Participants had a mean age of 59.6 (SD 10.6) years and 128/214 (59.8%) were men. No changes in MVPA time were observed from baseline to 52-week follow-up in the StC and IWT groups (least squares means [95% CI] 0.6 [-4.6 to 5.8] and -0.2 [-3.8 to 3.3], respectively) and no differences were observed between the groups (mean difference [95% CI] -0.8 [-8.1 to 6.4] minutes/day; P=.82). Physical HRQoL increased by a mean of 4.3 (95% CI 1.8 to 6.9) 12-item Short-Form Health Survey (SF-12) points more in the IWT group compared with the StC group (Benjamini-Hochberg adjusted P=.007) and waist circumference apparently decreased a mean of -2.3 (95% CI -4.1 to -0.4) cm more in the IWT group compared with the StC group but with a Benjamini-Hochberg adjusted P=.06. No between-group differences were observed among the remaining key secondary outcomes. Among individuals with T2D referred to municipality-based lifestyle programs, randomization to InterWalk app-based IWT did not increase objectively measured MVPA time over 52 weeks compared with standard health care, although apparent benefits were observed for physical HRQoL. ClinicalTrials.gov NCT02341690; https://clinicaltrials.gov/ct2/show/NCT02341690.


Magnetic fluid-filled microhole in the collapsed region of a photonic crystal fiber for the measurement of a magnetic field.
A method for measurement of a magnetic field by filling a microhole with magnetic fluid (MF) in a photonic crystal fiber (PCF) is presented and experimentally demonstrated. A microhole is created in the collapsed region between the PCF and the single-mode fiber by using femtosecond laser micromachining, and a PCF-based Mach-Zehnder interferometer is formed. The MF is filled into the microhole. Due to the tunable refractive index property of the MF, the mode field diameter of the propagation light is changed with the external magnetic field, and the magnetic field can be detected by measuring the visibility contrast of the white light interferogram. The experimental results show that sensitivity of up to 0.042 dB/Oe is achieved.


Reduced space constant in slowly conducting regions of chronically infarcted canine myocardium.
Experiments were performed to test the hypothesis that a reduction in the space constant contributes to slow conduction in the infarcted myocardium of dogs 5-8 days after coronary artery occlusion and reperfusion. Standard microelectrode techniques were used to measure action potential characteristics and conduction velocity parallel to fiber orientation in normal and infarcted ventricular epicardial strips superfused in a tissue bath. The space constants were determined by measuring the decay of the transmembrane steady state electrotonic potential with distance from a suction electrode current source. In eight normal epicardial preparations, conduction velocity ranged between 0.305 and 0.603 m/sec, and the space constant was between 0.712 and 1.202 mm. In 10 infarcted epicardial preparations, in regions of slow conduction (0.032-0.299 m/sec), the space constant was reduced to values between 0.281 and 0.917 mm. Action potential amplitude and maximum rate of depolarization were also reduced in infarcted myocardium. There was a direct relationship between conduction velocity and space constant and maximum rate of depolarization. In infarcted tissues, two types of slow conduction occurred. Slow conduction was uniform down to a velocity of approximately 0.181 m/sec, and a space constant of 0.523 mm. Below these values, conduction was discontinuous with prepotentials associated with the action potential upstroke. Indirect evidence from our studies suggests that a depression in action potential depolarization and an increase in effective axial resistance contribute approximately equally to uniform slow conduction in the infarcted myocardium.


Sperm chromatin packaging as an indicator of in-vitro fertilization rates.
The development of a sequential diagnostic schedule for patients consulting for infertility disturbances would be an ideal method of approach for clinicians in the absence of an aetiological or pathophysiological diagnosis. Since sperm morphology recorded by strict criteria has often been correlated with fertilization failure, the present study aimed to evaluate the relationship between normal morphology as well as in-vitro fertilization (IVF) rates, with chromatin staining among fertile and subfertile men. Two semen smears were prepared from each specimen obtained from 72 men to record normal morphology and chromatin packaging as recorded by chromomycin A(3) (CMA(3)) staining. Following the semen analyses, the 72 men were divided into the two morphological groups, namely <4% and >4% normal forms. Significantly different percentages of CMA(3) staining (mean +/- SE) were recorded between the two morphological groups, namely 65.9% +/- 3.5 and 44.5% +/- 1.7 (P +/- 0.001). A highly negative significant correlation existed between percentage of normal morphology as recorded by strict criteria and CMA(3) staining. A highly significant and positive correlation was recorded for normal morphology and IVF rates (r +/- 0.45, P +/- 0.0001). A significant negative correlation (r +/- -0.51, P +/- 0.0001) existed between CMA(3) values and IVF rates. The discriminating power of nuclear maturity, as recorded by CMA(3) staining, to identify abnormal morphology values and poor IVF rates was calculated with receiver operator characteristic (ROC) analyses. The areas under the ROC curves were 0.86 for sperm morphology and 0. 74 for IVF rates. The calculated threshold values for CMA(3) staining to distinguish between morphology groups were 48 and 50% for IVF. Chromatin packaging assessment is a valuable addition to the sequential diagnostic programme in an assisted reproductive arena.


Flipped classroom model improves graduate student performance in cardiovascular, respiratory, and renal physiology.
The purpose of this study was to assess the effectiveness of a traditional lecture-based curriculum versus a modified "flipped classroom" curriculum of cardiovascular, respiratory, and renal physiology delivered to first-year graduate students. Students in both courses were provided the same notes and recorded lectures. Students in the modified flipped classroom were required to watch the prerecorded lectures before class and then attend class, where they received a quiz or homework covering material in each lecture (valued at 25% of the final grade) followed by a question and answer/problem-solving period. In the traditional curriculum, attending lectures was optional and there were no quizzes. Evaluation of effectiveness and student performance was achieved by having students in both courses take the same multiple-choice exams. Within a comparable group of graduate students, participants in the flipped course scored significantly higher (P ≤ 0.05) on the cardiovascular, respiratory, and weighted cumulative sections by an average of >12 percentage points. Exam averages for students in the flipped course also tended to be higher on the renal section by ∼11 percentage points (P = 0.06). Based on our experience and responses obtained in blinded student surveys, we propose that the use of homework and in-class quizzes were critical motivating factors that likely contributed to the increase in student exam performance. Taken together, our findings support that the flipped classroom model is a highly effective means in which to disseminate key physiological concepts to graduate students.


What is the efficacy of switching to weekly pegvisomant in acromegaly patients well controlled on combination therapy?
Although combination therapy of acromegaly with long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV) normalizes insulin-like growth factor-1 (IGF1) levels in the majority of patients, it requires long-term adherence. Switching from combination therapy to monotherapy with weekly PEGV could improve patients' comfort, but the efficacy is unknown. To assess the efficacy of switching to PEGV monotherapy in patients well controlled on combination therapy of LA-SSAs and PEGV. Single-center, open-label observational pilot study. LA-SSA therapy was discontinued at baseline and all patients were switched to PEGV monotherapy for 12 months. If IGF1 levels exceeded 1.0 times upper limit of normal (ULN), PEGV dose was increased by 20 mg weekly. The study included 15 subjects (eight males), with a median age of 58 years (range 35-80) on combination therapy of high-dose LA-SSAs and weekly PEGV for >6 months, and IGF1 levels within the normal range. Treatment efficacy was assessed by measuring serum IGF1 levels. After 12 months of weekly PEGV monotherapy, serum IGF1 levels of 73% of the subjects remained controlled. In one patient, LA-SSA had to be restarted due to recurrence of headache. IGF1 levels increased from a baseline level of 0.62 × ULN (range 0.30-0.84) to 0.83 × ULN (0.30-1.75) after 12 months, while the median weekly PEGV dose increased from 60 (30-80) mg to 80 (50-120) mg. Our results suggest that switching from combination therapy of LA-SSAs and PEGV to PEGV monotherapy can be a viable treatment option for acromegaly patients without compromising efficacy.


Mannose-binding lectin may affect pregnancy outcome.
Mannose-binding lectin (MBL) is a component of the innate immune system and acts as a complement activator through the lectin pathway. Genetic variations of MBL and low MBL levels cause several infection problems, which may also be related to pregnancy problems. We aimed to investigate the role of MBL gene codon 54 polymorphism and serum MBL levels in pregnancy problems and premature delivery. In this prospective study, MBL gene codon 54 polymorphism and serum MBL levels were studied in 45 mothers who delivered earlier than 35 gestational weeks. The frequency of MBL gene codon 54 variant allele B was much higher (homozygous 4.4% and heterozygous 33.3%) in the study group mothers than the previously reported frequency in the healthy Turkish population (homozygous 2-6%, heterozygous 12-20%). MBL variant allele B frequency was closely related to low MBL levels (<0.1 μg/ml), vaginitis and increased IL-6 levels. The median MBL levels were lower than the critical level of 0.1 μg/ ml in study mothers who had recurrent miscarriage, infertility, preeclampsia, gestational diabetes mellitus, preterm premature rupture of membranes with duration of longer than 72 hours, tocolysis, histological chorioamnionitis, urinary tract infection and vaginitis. MBL gene codon 54 variant allele B is related to low serum MBL levels, increased IL-6 levels, genitourinary infections and may cause pregnancy-related problems such as infertility, recurrent miscarriage and preterm delivery.


A Devonian predatory fish provides insights into the early evolution of modern sarcopterygians.
Crown or modern sarcopterygians (coelacanths, lungfishes, and tetrapods) differ substantially from stem sarcopterygians, such as Guiyu and Psarolepis, and a lack of transitional fossil taxa limits our understanding of the origin of the crown group. The Onychodontiformes, an enigmatic Devonian predatory fish group, seems to have characteristics of both stem and crown sarcopterygians but is difficult to place because of insufficient anatomical information. We describe the new skull material of Qingmenodus, a Pragian (~409-million-year-old) onychodont from China, using high-resolution computed tomography to image internal structures of the braincase. In addition to its remarkable similarities with stem sarcopterygians in the ethmosphenoid portion, Qingmenodus exhibits coelacanth-like neurocranial features in the otic region. A phylogenetic analysis based on a revised data set unambiguously assigns onychodonts to crown sarcopterygians as stem coelacanths. Qingmenodus thus bridges the morphological gap between stem sarcopterygians and coelacanths and helps to illuminate the early evolution and diversification of crown sarcopterygians.


Neuronal lactate levels depend on glia-derived lactate during high brain activity in Drosophila.
Lactate/pyruvate transport between glial cells and neurons is thought to play an important role in how brain cells sustain the high-energy demand that neuronal activity requires. However, the in vivo mechanisms and characteristics that underlie the transport of monocarboxylates are poorly described. Here, we use Drosophila expressing genetically encoded FRET sensors to provide an ex vivo characterization of the transport of monocarboxylates in motor neurons and glial cells from the larval ventral nerve cord. We show that lactate/pyruvate transport in glial cells is coupled to protons and is more efficient than in neurons. Glial cells maintain higher levels of intracellular lactate generating a positive gradient toward neurons. Interestingly, during high neuronal activity, raised lactate in motor neurons is dependent on transfer from glial cells mediated in part by the previously described monocarboxylate transporter Chaski, providing support for in vivo glia-to-neuron lactate shuttling during neuronal activity.


Stakeholders' Perceptions on Shortage of Healthcare Workers in Primary Healthcare in Botswana: Focus Group Discussions.
An adequate health workforce force is central to universal health coverage and positive public health outcomes. However many African countries have critical shortages of healthcare workers, which are worse in primary healthcare. The aim of this study was to explore the perceptions of healthcare workers, policy makers and the community on the shortage of healthcare workers in Botswana. Fifteen focus group discussions were conducted with three groups of policy makers, six groups of healthcare workers and six groups of community members in rural, urban and remote rural health districts of Botswana. All the participants were 18 years and older. Recruitment was purposive and the framework method was used to inductively analyse the data. There was a perceived shortage of healthcare workers in primary healthcare, which was believed to result from an increased need for health services, inequitable distribution of healthcare workers, migration and too few such workers being trained. Migration was mainly the result of unfavourable personal and family factors, weak and ineffective healthcare and human resources management, low salaries and inadequate incentives for rural and remote area service. Botswana has a perceived shortage of healthcare workers, which is worse in primary healthcare and rural areas, as a result of multiple complex factors. To address the scarcity the country should train adequate numbers of healthcare workers and distribute them equitably to sufficiently resourced healthcare facilities. They should be competently managed and adequately remunerated and the living conditions and rural infrastructure should also be improved.


MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells.
The Brg/Brahma-associated factor (BAF, mSWI/SNF) chromatin remodeling complex is of importance in development and has been linked to prostate oncogenesis. The oncogenic MUC1-C protein promotes lineage plasticity in the progression of neuroendocrine prostate cancer (NEPC), however, there is no known association between MUC1-C and BAF. We report here that MUC1-C binds directly to the E2F1 transcription factor and that the MUC1-C→E2F1 pathway induces expression of embryonic stem cell-specific BAF (esBAF) components BRG1, ARID1A, BAF60a, BAF155, and BAF170 in castrate-resistant prostate cancer (CRPC) and NEPC cells. In concert with this previously unrecognized pathway, MUC1 was associated with increased expression of E2F1 and esBAF components in NEPC tumors as compared with CRPC, supporting involvement of MUC1-C in activating the E2F1→esBAF pathway with progression to NEPC. MUC1-C formed a nuclear complex with BAF and activated cancer stem cell (CSC) gene signatures and the core pluripotency factor gene network. The MUC1-C→E2F1→BAF pathway was necessary for induction of both the NOTCH1 effector of CSC function and the NANOG pluripotency factor, and collectively, this network drove CSC self-renewal. These findings indicate that MUC1-C promotes NEPC progression by integrating activation of E2F1 and esBAF with induction of NOTCH1, NANOG, and stemness. SIGNIFICANCE: These findings show that MUC1-C, which promotes prostate cancer progression, activates a novel pathway that drives the BAF remodeling complex, induces NOTCH1 and NANOG, and promotes self-renewal of prostate cancer stem cells.


Glucocorticoids at the Olympic Games: state-of-the-art review.
In this state-of-the-art review, the author discusses the history of prohibiting glucocorticoids (GCs) and how this has occurred over nearly three decades at the Olympic Games. He relates how prohibiting systemic GCs in sport was a major factor in the development of therapeutic use exemptions and the fluctuating status of non-systemic GCs (banned, not banned). Concern is expressed that for 2017, the World Anti-Doping Agency (WADA) is proposing to prohibit injecting GCs shortly prior to competition. The author notes that in 1986, when GCs were first prohibited, analytical chemistry techniques could not distinguish the route of GC administration from its urinary concentration. Thirty years later, this remains the case. Importantly, this article discusses how the desired pharmacological effects of injecting GCs locally and intra-articularly can be achieved and why exercising vigorously immediately or shortly after a GC injection is therapeutically unsound. The review concludes by agreeing that injecting GCs shortly prior to strenuous training or competition is medically unwise but stresses that this is a clinical matter that sport-not WADA-needs to address. Cycling and rowing have managed this successfully for the past 5 years.


S-adenosyl methionine prevents promiscuous DNA cleavage by the EcoP1I type III restriction enzyme.
DNA cleavage by the type III restriction endonuclease EcoP1I was analysed on circular and catenane DNA in a variety of buffers with different salts. In the presence of the cofactor S-adenosyl methionine (AdoMet), and irrespective of buffer, only substrates with two EcoP1I sites in inverted repeat were susceptible to cleavage. Maximal activity was achieved at a Res2Mod2 to site ratio of approximately 1:1 yet resulted in cleavage at only one of the two sites. In contrast, the outcome of reactions in the absence of AdoMet was dependent upon the identity of the monovalent buffer components, in particular the identity of the cation. With Na+, cleavage was observed only on substrates with two sites in inverted repeat at elevated enzyme to site ratios (>15:1). However, with K+ every substrate tested was susceptible to cleavage above an enzyme to site ratio of approximately 3:1, including a DNA molecule with two directly repeated sites and even a DNA molecule with a single site. Above an enzyme to site ratio of 2:1, substrates with two sites in inverted repeat were cleaved at both cognate sites. The rates of cleavage suggested two separate events: a fast primary reaction for the first cleavage of a pair of inverted sites; and an order-of-magnitude slower secondary reaction for the second cleavage of the pair or for the first cleavage of all other site combinations. EcoP1I enzymes mutated in either the ATPase or nuclease motifs did not produce the secondary cleavage reactions. Thus, AdoMet appears to play a dual role in type III endonuclease reactions: Firstly, as an allosteric activator, promoting DNA association; and secondly, as a "specificity factor", ensuring that cleavage occurs only when two endonucleases bind two recognition sites in a designated orientation. However, given the right conditions, AdoMet is not strictly required for DNA cleavage by a type III enzyme.


Suicide Prevention Strategies for General Hospital and Psychiatric Inpatients: A Narrative Review.
In-patient (IP) suicides contribute a small but significant proportion of overall suicides. Despite this, suicide prevention strategies focusing on the general hospital IP population remain relatively underresearched. This paper is intended to provide an overview of various proposed suicide prevention approaches in the general hospital, including psychiatric IP, settings, and their evidence base. Electronic searches of MEDLINE through PubMed, ScienceDirect, and Google Scholar databases were performed to identify potentially relevant articles from inception till January 2019. The generated abstracts were systematically screened for their eligibility to be included in the review. Included articles were grouped under five broad themes: environmental modification, staff education, pharmacotherapy, psychotherapy, and brain stimulation. Data extraction was done using a structured proforma. Environmental modifications and educating the health care professionals appear to be the most promising strategies to reduce suicide-related mortality among IPs. Among pharmacological methods, ketamine has shown initial promise in reducing suicidal ideations. Follow-up data are lacking for most of the described methods. Limited but positive evidence exists for cognitive therapies focusing on the immediate postadmission period and brain stimulation techniques, and it warrants further replication. There is a striking paucity of original research on IP suicide prevention. Given the ethical and methodological issues in carrying out studies with IP suicide as the primary outcome, there is a need to focus on intermediate suicide outcome measures, such as knowledge, attitude, and skills among staff handlers of suicidal patients.


Analytical extraction of leaky modes in circular slab waveguides with arbitrary refractive index profile.
Circular slab waveguides are conformally transformed into straight inhomogeneous waveguides, whereupon electromagnetic fields in the core are expanded in terms of Legendre polynomial basis functions. Thereafter, different analytical expression of electromagnetic fields in the cladding region, viz. Wentzel-Kramers-Brillouin solution, modified Airy function expansion, and the exact field solution for circular waveguides, i.e., Hankel function of complex order, are each matched to the polynomial expansion of the transverse electric field within the guide. This field matching process renders different boundary conditions to be satisfied by the set of orthogonal Legendre polynomial basis functions. In this fashion, the governing wave equation is converted into an algebraic and easy to solve eigenvalue problem, which is associated with a matrix whose elements are analytically given. Various numerical examples are presented and the accuracy of each of the abovementioned different boundary conditions is assessed. Furthermore, the computational efficiency and the convergence rate of the proposed method with increasing number of basis functions are briefly discussed.


Angular scattering from optical interference coatings: scalar scattering predictions and measurements.
A scalar scattering theory is developed that predicts the angular distribution of light scattered and the total integrated scatter from a randomly rough or inhomogeneous optical interference coating. Three types of random variation are considered: uncorrelated roughness, additive roughness, and uncorrelated index inhomogeneity. The scattering calculations are formulated so that the output of any conventional thin film analysis program along with a coating's surface or index statistics could be used to calculate the scattering distribution of a coating. The scattering calculations are compared to experimental measurements from a sixteen-layer high reflector coating with small additive roughness sigma = 2.4 A and large correlated roughness sigma = 93 A.


Two-photon focal modulation microscopy for high-resolution imaging in deep tissue.
Two-photon microscopy (2PM) is one of the most widely used tools for in vivo deep tissue imaging. However, the spatial resolution and penetration depth are still limited due to the strong scattering background. Here we demonstrate a two-photon focal modulation microscopy. By utilizing the modulation and demodulation techniques, background rejection capability is enhanced, thus spatial resolution and imaging penetration depth are improved. Compared with 2PM, the transverse resolution is increased by 70%, while the axial resolution is increased to 2-fold. Furthermore, when applied in conventional 2PM mode, it can achieve inertial-free scanning in either transverse or axial direction with in principle unlimited scanning speed. Finally, we applied 2PFMM in thick scattering samples to further examine the imaging performance. The results show that the signal-to-background ratio of 2PFMM can be improved up to five times of 2PM at the depth of 500 μm. Fluorescent imaging in the mouse brain tissue. 3D Thy1-GFP hippocampal neurons imaged by (A) 2PM compared with (B) 2PFMM; (C-H) xy maximum-intensity projection imaged by 2PM compared with 2PFMM. Scale bar 50 μm.


The effects of acoustical refurbishment of classrooms on teachers' perceived noise exposure and noise-related health symptoms.
To investigate whether acoustical refurbishment of classrooms for elementary and lower secondary grade pupils affected teachers' perceived noise exposure during teaching and noise-related health symptoms. Two schools (A and B) with a total of 102 teachers were subjected to an acoustical intervention. Accordingly, 36 classrooms (20 and 16 in school A and school B, respectively) were acoustically refurbished and 31 classrooms (16 and 15 in school A and school B, respectively) were not changed. Thirteen classrooms in school A were interim "sham" refurbished. Control measurements of RT and activity sound levels were measured before and after refurbishment. Data on perceived noise exposure, disturbance attributed to different noise sources, voice symptoms, and fatigue after work were collected over a year in a total of six consecutive questionnaires. Refurbished classrooms were associated with lower perceived noise exposure and lower ratings of disturbance attributed to noise from equipment in the class compared with unrefurbished classrooms. No associations between the classroom refurbishment and health symptoms were observed. Before acoustical refurbishment, the mean classroom reverberation time was 0.68 (school A) and 0.57 (school B) and 0.55 s in sham refurbished classrooms. After refurbishment, the RT was approximately 0.4 s in both schools. Activity sound level measurements confirmed that the intervention had reduced the equivalent sound levels during lessons with circa 2 dB(A) in both schools. The acoustical refurbishment was associated with a reduction in classroom reverberation time and activity sound levels in both schools. The acoustical refurbishment was associated with a reduction in the teachers' perceived noise exposure, and reports of disturbance from equipment in the classroom decreased. There was no significant effect of the refurbishment on the teachers' voice symptoms or fatigue after work.


Repellency property of long chain aliphatic methyl ketones against Anopheles gambiae s.s.
Long chain aliphatic methyl ketone series of C7-C15 were tested for repellency activity against the malaria transmitting mosquito Anopheles gambiae s.s. All methyl ketones produced a dose dependent (P < 0.001) repellency response with 2-tridecanone giving comparable protection efficacy to DEET at 10% and 1% concentrations. Aliphatic methyl ketones of C7-C10 had lower activity than those of C11-C15. However, within this range compounds with odd carbon atoms (2-undecanone, 2-tridecanone and 2-pentadecanone) were more effective than compounds with even carbon atoms (2-decanone and 2- dodecanone). Comparable repellency activity of 2-tridecanone to DEET show that, it may save as Anopheles gambiae s.s. mosquito repellent.


Registered access: authorizing data access.
The Global Alliance for Genomics and Health (GA4GH) proposes a data access policy model-"registered access"-to increase and improve access to data requiring an agreement to basic terms and conditions, such as the use of DNA sequence and health data in research. A registered access policy would enable a range of categories of users to gain access, starting with researchers and clinical care professionals. It would also facilitate general use and reuse of data but within the bounds of consent restrictions and other ethical obligations. In piloting registered access with the Scientific Demonstration data sharing projects of GA4GH, we provide additional ethics, policy and technical guidance to facilitate the implementation of this access model in an international setting.


Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes.
This paper shows that melatonin is able to activate human Th1 lymphocytes by increasing the production of IL-2 and IFN-gamma in vitro. Th2 cells appear not to be affected by melatonin, since IL-4, which is mostly produced by Th2 cells, is not modified by the hormone. Melatonin also enhances IL-6 production by PBMCs. The activation by melatonin of IL-6 production is apparently related to the presence of monocytes, rather than to Th2 cells, in the cell preparation, since PBMCs depleted of monocytes (CD14+ cells) were not activated. Activation of PBMCs by melatonin was dependent on the dose and, measured by cytokine production, was observed only when cells were either not activated or only slightly activated by low concentrations of PHA, or when cell activation was achieved by incubating the cells with previously irradiated cells. Using a different approach to identify what type of cells among the PBMC subsets was activated by melatonin, the expression of CD69, a marker of cell activation, was studied. Melatonin increased the percentage of cells expressing the CD69 Ag in CD4+ but not in CD8+ cells. We have also achieved enhanced production of IL-2 and IL-6 using CGP 52608, a specific ligand of the putative nuclear melatonin receptor RZR/ROR, raising the possibility of direct effects of melatonin on gene regulation in both Th1 cells and monocytes. The results suggest that melatonin may be involved in the regulation of human immune functions by modulating the activity of Th1 cells and monocytes via nuclear receptor-mediated transcriptional control.


Feeling Better When Someone Is Alike: Poor Emotion Regulators Profit From Pro-Social Values and Priming for Similarities With Close Others.
The dispositional inability to self-regulate one's own emotions intuitively is described as state orientation and has been associated with numerous psychological impairments. The necessity to search for buffering effects against negative outcomes of state orientation is evident. Research suggests that state-oriented individuals can benefit from feeling close to others. Yet, there are individual differences in the extent to which supportive relationships are valued. The objective of the present article was to examine whether high importance of relatedness increases the utilization of its situational activation among state-oriented individuals. In two studies, we examined whether situational activation of relatedness (by priming for similarities with a close other) is particularly advantageous for state-oriented individuals who attach high importance to relatedness (i.e., benevolence values). The sample consisted of 170 psychology undergraduates in Study 1 and 177 in Study 2. In both studies, state-oriented participants high in benevolence had reduced negative mood after thinking about similarities (vs. differences). State-oriented participants low in benevolence did not benefit from priming for similarities. In Study 2, physical presence of a close other did not boost priming effects for state-oriented participants but stimulated action-oriented participants to attune their self-regulatory efforts to the context. The results show that state-oriented individuals who value benevolence do benefit from a situational activation of relatedness.


Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues.
Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.


Indicators of moisture and ventilation system contamination in U.S. office buildings as risk factors for respiratory and mucous membrane symptoms: analyses of the EPA BASE data.
We assessed associations between indicators for moisture in office buildings and weekly, building-related lower respiratory and mucous membrane symptoms in office workers, using the U.S. EPA BASE data, collected in a representative sample of 100 U.S. office buildings. We estimated the strength of associations between the symptom outcomes and moisture indicators in multivariate logistic regression models as odds ratios (ORs) and 95% confidence intervals (CI), controlling for potential confounding factors and adjusting for correlation among workers in buildings. This analysis identified associations between building-related symptoms and several indicators of moisture or contamination in office buildings. One set of models showed almost a tripling of weekly building-related lower respiratory symptoms in association with lack of cleaning of the drip pans under air-conditioning cooling coils (OR [CI] = 2.8 (1.2-6.5)). Other models found that lack of cleaning of either drip pans or cooling coils was associated with increased mucous membrane symptoms (OR [CI] = 1.4 (1.1-1.9)). Slightly increased symptoms were also associated with other moisture indicators, especially mucous membrane symptoms and past water damage to building mechanical rooms (OR [CI] = 1.3 (1.0-1.7)). Overall, these findings suggest that the presence of moisture or contamination in ventilation systems or occupied spaces in office buildings may have adverse respiratory or irritant effects on workers. The analysis, however, failed to confirm several risks identified in a previous study, such as condition of drain pans or outdoor air intakes, and other hypothesized moisture risks. Studies with more rigorous measurement of environmental risks and health outcomes will be necessary to define moisture-related risks in buildings.


pH- and ligand-induced release of loads from DNA-acrylamide hydrogel microcapsules.
Herein, a method to construct stimuli-responsive DNA-acrylamide-based hydrogel microcapsules has been presented. This method involves the use of polyacrylamide chains modified with predesigned nucleic acid hairpin units and optionally single-strand tethers that provide the required hybridization and recognition functions to yield substrate-loaded stimuli-responsive hydrogel-based microcapsules. The synthesis of the microcapsules involves the loading of CaCO3 microparticles with the respective load substrates and the functionalization of the CaCO3 template particles with nucleic acid promoter units. In the presence of the hairpin-modified acrylamide chains, the promoter units induce the hybridization chain reaction (HCR), which leads to the formation of a hydrogel coating, which, after the dissociation of the CaCO3 cores, yields substrate-loaded stimuli-responsive hydrogel microcapsules. One of the microcapsule systems includes, in the hairpin-modified acrylamide constructs, and in the subsequent HCR-generated hydrogel shells, the caged sequences of anti-ATP or anti-cocaine aptamers. In the presence of ATP or cocaine, the duplex-caged aptamer sequences are separated via the formation of ATP- or cocaine-aptamer complexes, which results in the partial separation of the microcapsules and the release of the loads. The second type of microcapsule is cooperatively stabilized by bridges generated by HCR and pH-sensitive duplex units. Under acidic conditions, the pH-sensitive bridges dissociate via the formation of i-motif structures, which results in an increase in the fluidity of the microcapsule shells and the release of the loads. Preliminary studies indicate that ATP- or pH-responsive microcapsules loaded with the anticancer drug, doxorubicin, have a selective cytotoxic effect on MDA-MB-231 cancer cells.


The association of birthweight and contemporary size with insulin resistance among children from Estonia and Denmark: findings from the European Youth Heart Study.
To assess the associations of birthweight, contemporary body mass index and height with insulin resistance in children. Cross-sectional study. From Estonia (n = 1174) and Denmark (n = 1018), 2192 school children aged 9 and 15 years were randomly selected. Insulin resistance (homeostasis model assessment), triglyceride levels, high-density lipoprotein cholesterol and systolic blood pressure. There was an inverse association between birthweight and insulin resistance and a positive association between contemporary body mass index and insulin resistance. With adjustment for maternal and paternal educational level, income, smoking and body mass index, an increase of one unit of sex, age and country standardized body mass index z-score was associated with a 5% (95% CI: 2, 7%) increase in homeostasis model assessment (HOMA) score and a one-unit z-score increase in birthweight with a 2% (95% CI: 0, 5%) decrease in HOMA score. In the 9-year-old age group, height was positively associated with insulin resistance [for a one-unit increase in height z-score HOMA score increased by 30% (95% CI: 14, 50%)], but in the 15-year-old age group there was no association between height and insulin resistance (4% (95% CI: -5, 14%), P for interaction with age group = 0.001). For both ages, those in the lowest third of the birthweight distribution and highest third of the body mass index distribution were most insulin resistant and, among 9-year olds, those in the lowest third of the birthweight distribution and highest third of the height distribution were most insulin resistant. Birthweight was only inversely associated with systolic blood pressure when adjustment was made for either contemporary body mass index or height and there was no association between birthweight and high-density lipoprotein or triglyceride concentrations. Taken together, these results suggest that a slow intrauterine growth trajectory and/or a fast post-natal growth trajectory is associated with greater insulin resistance in childhood.


Molecular basis of nucleotide-dependent substrate engagement and remodeling by an AAA+ activator.
Binding and hydrolysis of ATP is universally required by AAA+ proteins to underpin their mechano-chemical work. Here we explore the roles of the ATPase site in an AAA+ transcriptional activator protein, the phage shock protein F (PspF), by specifically altering the Walker B motif sequence required in catalyzing ATP hydrolysis. One such mutant, the E108Q variant, is defective in ATP hydrolysis but fully remodels target transcription complexes, the RNAP-σ(54) holoenzyme, in an ATP dependent manner. Structural analysis of the E108Q variant reveals that unlike wild-type protein, which has distinct conformations for E108 residue in the ATP and ADP bound forms, E108Q adapts the same conformation irrespective of nucleotide bound. Our data show that the remodeling activities of E108Q are strongly favored on pre-melted DNA and engagement with RNAP-σ(54) using ATP binding can be sufficient to convert the inactive holoenzyme to an active form, while hydrolysis per se is required for nucleic acid remodeling that leads to transcription bubble formation. Furthermore, using linked dimer constructs, we show that RNAP-σ(54) engagement by adjacent subunits within a hexamer are required for this protein remodeling activity while DNA remodeling activity can tolerate defective ATP hydrolysis of alternating subunits.


Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.
Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects. We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families. We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA. Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA. We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.


Epidemiology, prehospital care and outcomes of patients arriving by ambulance with dyspnoea: an observational study.
This study aimed to determine epidemiology and outcome for patients presenting to emergency departments (ED) with shortness of breath who were transported by ambulance. This was a planned sub-study of a prospective, interrupted time series cohort study conducted at three time points in 2014 and which included consecutive adult patients presenting to the ED with dyspnoea as a main symptom. For this sub-study, additional inclusion criteria were presentation to an ED in Australia or New Zealand and transport by ambulance. The primary outcomes of interest are the epidemiology and outcome of these patients. Analysis was by descriptive statistics and comparisons of proportions. One thousand seven patients met inclusion criteria. Median age was 74 years (IQR 61-68) and 46.1 % were male. There was a high rate of co-morbidity and chronic medication use. The most common ED diagnoses were lower respiratory tract infection (including pneumonia, 22.7 %), cardiac failure (20.5%) and exacerbation of chronic obstructive pulmonary disease (19.7 %). ED disposition was hospital admission (including ICU) for 76.4 %, ICU admission for 5.6 % and death in ED in 0.9 %. Overall in-hospital mortality among admitted patients was 6.5 %. Patients transported by ambulance with shortness of breath make up a significant proportion of ambulance caseload and have high comorbidity and high hospital admission rate. In this study, >60 % were accounted for by patients with heart failure, lower respiratory tract infection or COPD, but there were a wide range of diagnoses. This has implications for service planning, models of care and paramedic training. This study shows that patients transported to hospital by ambulance with shortness of breath are a complex and seriously ill group with a broad range of diagnoses. Understanding the characteristics of these patients, the range of diagnoses and their outcome can help inform training and planning of services.


Environmentally Friendly and Biodegradable Ultrasensitive Piezoresistive Sensors for Wearable Electronics Applications.
Highly sensitive, flexible sensors that can be manufactured with minimum environmental footprint and be seamlessly integrated into wearable devices are required for real-time tracking of complex human movement, gestures, and health conditions. This study reports on how biodegradation can be used to enhance the sensitivity and electromechanical performance of piezoresistive sensors. Poly(glycerol sebacate) (PGS) elastomeric porous sensor was synthesized and blended with multiwall carbon nanotubes (MWCNTs) and sodium chloride (NaCl). Because of their unique porous characteristics, a single linear behavior over a large range of pressures (≤8 kPa) and an increase in their sensitivity from 0.12 ± 0.03 kPa-1 up to 8.00 ± 0.20 kPa-1 was achieved after 8 weeks in a simulated body fluid media. They can detect very low pressures (100 Pa), with negligible hysteresis, reliability, long lifetime (>200 000 cycles), short response time (≤20 ms), and high force sensitivity (≤4 mN). The characteristics of the developed foam sensors match the sensing characteristics of the human finger to pave the way toward low-footprint wearable devices for applications including human movement and condition monitoring, recreation, health and wellness, virtual reality, and tissue engineering.


Structure of the liquid-vacuum interface of room-temperature ionic liquids: a molecular dynamics study.
Molecular dynamics simulations for the liquid-vacuum interface of the ionic liquid 1-ethyl-3-methylimidazolium nitrate (EMIM+/NO3-) were performed for both electronically polarizable and nonpolarizable potential energy surfaces. The interfacial structural properties, such as the oscillation in the number density profile, the orientational ordering, and the local clustering in the interfacial region, were calculated. The simulations with both the polarizable and nonpolarizable model demonstrate the existence of an inhomogeneous interfacial structure normal to the surface layer. It was found for both models that the ethyl tail group on EMIM+ is likely to protrude outward from the surface. In the outmost surface layer, the cation is likely to lie on the surface with the imidazolium ring parallel to the interface, while there is a second region with enhanced density from that in the bulk where the cation preferably slants with the imidazolium ring tending to be perpendicular to the surface. The results also reveal that the electronic polarization effect is important for the ionic liquid interface. It is found that the cation is likely to be segregated at the ionic liquid surface for the polarizable model, while for the nonpolarizable model, the anion is found to be more likely to exhibit such behavior. The surface tension of the polarizable model (58.5 +/- 0.5 mN/m) is much smaller than that of the nonpolarizable model (82.7 +/- 0.6 mN/m), in better agreement with extrapolated experimental measurements on similar ionic liquid systems.


Temporal temperature gradient electrophoresis for detection of single nucleotide polymorphisms.
The presence of single nucleotide polymorphisms (SNPs) in nuclear DNA and mitochondrial DNA (mtDNA) can be detected using a range of electrophoretic techniques, of which temporal temperature gradient electrophoresis (TTGE) is often the most user-friendly and reproducible. The technique operates on the same principle as denaturing gradient gel electrophoresis, but does not require a chemical gradient in the gel. Instead, TTGE relies on a steady and gradual increase in temperature during electrophoresis to denature and separate DNA sequences that differ by as little as one base pair. TTGE can be easily accomplished using DNA of high quality and it is a rapid-throughput method for SNP screening once conditions have been optimized. Detection of SNPs is, for example, important for the diagnosis of mitochondrial disorders such as heteroplasmy, the presence of more than one type of mitochondria within a cell or tissue. Here we describe the basic steps for TTGE and illustrate its utility for the detection of heteroplasmy in mtDNA control region sequences.


Trends in local newspaper reporting of London cyclist fatalities 1992-2012: the role of the media in shaping the systems dynamics of cycling.
Successfully increasing cycling across a broad range of the population would confer important health benefits, but many potential cyclists are deterred by fears about traffic danger. Media coverage of road traffic crashes may reinforce this perception. As part of a wider effort to model the system dynamics of urban cycling, in this paper we examined how media coverage of cyclist fatalities in London changed across a period when the prevalence of cycling doubled. We compared this with changes in the coverage of motorcyclist fatalities as a control group. Police records of traffic crashes (STATS19) were used to identify all cyclist and motorcyclist fatalities in London between 1992 and 2012. We searched electronic archives of London's largest local newspaper to identify relevant articles (January 1992-April 2014), and sought to identify which police-reported fatalities received any media coverage. We repeated this in three smaller English cities. Across the period when cycling trips doubled in London, the proportion of fatalities covered in the local media increased from 6% in 1992-1994 to 75% in 2010-2012. By contrast, the coverage of motorcyclist fatalities remained low (4% in 1992-1994 versus 5% in 2010-2012; p=0.007 for interaction between mode and time period). Comparisons with other English cities suggested that the changes observed in London might not occur in smaller cities with lower absolute numbers of crashes, as in these settings fatalities are almost always covered regardless of mode share (79-100% coverage for both cyclist and motorcyclist fatalities). In large cities, an increase in the popularity (and therefore 'newsworthiness') of cycling may increase the propensity of the media to cover cyclist fatalities. This has the potential to give the public the impression that cycling has become more dangerous, and thereby initiate a negative feedback loop that dampens down further increases in cycling. Understanding these complex roles of the media in shaping cycling trends may help identify effective policy levers to achieve sustained growth in cycling.


Using the chicken embryo to assess virulence of Listeria monocytogenes and to model other microbial infections.
Microbial infections are a global health problem, particularly as microbes are continually developing resistance to antimicrobial treatments. An effective and reliable method for testing the virulence of different microbial pathogens is therefore a useful research tool. This protocol describes how the chicken embryo can be used as a trustworthy, inexpensive, ethically desirable and quickly accessible model to assess the virulence of the human bacterial pathogen Listeria monocytogenes, which can also be extended to other microbial pathogens. We provide a step-by-step protocol and figures and videos detailing the method, including egg handling, infection strategies, pathogenicity screening and isolation of infected organs. From the start of incubation of the fertilized eggs, the protocol takes <4 weeks to complete, with the infection part taking only 3 d. We discuss the appropriate controls to use and potential adjustments needed for adapting the protocol for other microbial pathogens.


Factors influencing the size of PEO complexes with a tyrosine-rich polypeptide.
Aqueous complexes of PEY1, a 36 100 Da random synthetic peptide of tyrosine (50 mol %) and glutamic acid (50 mol %), with poly(ethylene oxide) (PEO) were studied as functions of PEO molecular weight, mixing ratio of PEO and PEY1, and the presence of calcium ions. Without calcium ions, the complexes were water soluble, with each complex consisting of a single PEO chain with many bound PEY1 chains. In the presence of 1 mM calcium ions, PEY1 formed colloidal aggregates with intermediate molecular weight PEO (10(5) to 10(6) Da). By contrast, very high molecular weight PEO (8 x 10(6) Da) with calcium ions formed large hydrogels when mixed with PEY1. It is proposed that PEY1 molecules completely bind to low molecular PEO and thus are deactivated from causing the coupling of multiple PEO chains, whereas deactivation of PEY1 on very high molecular weight PEO clusters is a slower process, giving an opportunity for cluster-cluster aggregation.


Reporting of key methodological issues in placebo-controlled trials of surgery needs improvement: a systematic review.
To examine key methodological considerations for using a placebo intervention in randomized controlled trials (RCTs) evaluating invasive procedures, including surgery. RCTs comparing an invasive procedure with a placebo were included in this systematic review. Articles published from database inception to December 31, 2017, were retrieved from Ovid MEDLINE, Ovid EMBASE and CENTRAL electronic databases, by handsearching references and expert knowledge. Data on trial characteristics (clinical area, nature of invasive procedure, number of patients and centers) and key methodological (rationale for using placebos, minimization of risk, information provision, offering the treatment intervention to patients randomized to placebo, delivery of cointerventions, and intervention standardization and fidelity) were extracted and summarized descriptively. One hundred thirteen articles reporting 96 RCTs were identified. Most were conducted in gastrointestinal surgery (n = 40, 42%) and evaluated minimally invasive procedures (n = 44, 46%). Over two-thirds randomized fewer than 100 patients (n = 65, 68%) and a third were single center (n = 31, 32%). A third (n = 33, 34%) did not report a rationale for using a placebo. Most common strategies to minimize patient risk were operator skill (n = 22, 23%) and independent data monitoring (n = 28, 29%). Provision of patient information regarding placebo use was infrequently reported (n = 11, 11%). Treatment interventions were offered to patients randomized to placebo in 43 trials (45%). Cointerventions were inconsistently reported, but 64 trials (67%) stated that anesthesia was matched between groups. Attempts to standardize interventions and monitor their delivery were reported in n = 7, (7%) and n = 4, (4%) trials, respectively. Most placebo-controlled trials in surgery evaluate minor surgical procedures and currently there is inconsistent reporting of key trial methods. There is a need for guidance to optimize the transparency of trial reporting in this area.


On the distribution of interspecies correlation for Markov models of character evolution on Yule trees.
Efforts to reconstruct phylogenetic trees and understand evolutionary processes depend fundamentally on stochastic models of speciation and mutation. The simplest continuous-time model for speciation in phylogenetic trees is the Yule process, in which new species are "born" from existing lineages at a constant rate. Recent work has illuminated some of the structural properties of Yule trees, but it remains mostly unknown how these properties affect sequence and trait patterns observed at the tips of the phylogenetic tree. Understanding the interplay between speciation and mutation under simple models of evolution is essential for deriving valid phylogenetic inference methods and gives insight into the optimal design of phylogenetic studies. In this work, we derive the probability distribution of interspecies covariance under Brownian motion and Ornstein-Uhlenbeck models of phenotypic change on a Yule tree. We compute the probability distribution of the number of mutations shared between two randomly chosen taxa in a Yule tree under discrete Markov mutation models. Our results suggest summary measures of phylogenetic information content, illuminate the correlation between site patterns in sequences or traits of related organisms, and provide heuristics for experimental design and reconstruction of phylogenetic trees.


Western Australia facing critical losses in its midwifery workforce: a survey of midwives' intentions.
the ongoing attrition of the midwifery workforce frustrates future workforce planning and the provision of maternity services in Western Australia. This project determined factors contributing to the intention of the midwives to move jobs and/or leave the profession. a cross-sectional survey approach was taken for this descriptive research utilising a self-administered questionnaire developed by the Nursing and Midwifery Office, Department of Health, Western Australia. public and private health sectors in Western Australia, April-May 2010. 1,600 midwives employed in the public and private health sectors throughout Western Australia were invited to participate: 712 responded (44.5%), one-fifth of the state's registered midwives. most midwives worked part-time in a clinical role in public hospitals. Almost half intended moving jobs within 5 years and/or leaving midwifery. Excluding midwives of retirement age, the most common reasons for intending to move jobs were family commitments, working conditions and role dissatisfaction. Those intending to leave midwifery cited work-life balance, career change and family commitments. Midwives thought addressing the following issues would improve midwifery retention: flexible work arrangements, remuneration, staffing and caseload, workplace culture, professional development and models of care. retaining the midwifery workforce requires attention to workforce practices particularly flexible work arrangements and workloads; models of care to strengthen midwives' relationships with clients and colleagues; and accessible professional development. a review of workplace practices at unit and institution levels is urgently required in Western Australia so that midwives can achieve work-life balance and practice to the full extent of their professional role. These changes are necessary to forestall premature retirement of skilled and experienced midwives from the profession and workforce churn.


Scattering from nonspherical Chebyshev particles. 3: Variability in angular scattering patterns.
We study shape-induced variability in the scattered intensity from randomly oriented nonspherical particles. Up to 21 different Chebyshev shapes contribute to defining a shape-induced standard deviation about each of the mean nonspherical intensity vs angle curves shown in part 2 of this series. Bands of shape-induced variability (defined as plus and minus one standard deviation) for six size intervals within the size parameter range 1 </= x </= 20 are compared with corresponding spherical intensities. Averaging spherical intensities over narrow size ranges produces effects qualitatively similar to mildly distorting a single sphere. Nevertheless, among all shapes, the sphere is often the most anomalous scatterer; nonspherical scattered intensities tend to be closer to one another than to corresponding spherical intensities. For Chebyshev particles which are neither small nor large compared to the wavelength, shape-induced variability is often comparable to the mean. Furthermore, outside the forward-scattering reg ion, this variability is large relative to the deformation from a sphere. The standard deviation is up to 50% of the mean scattered intensity for particles with an average deformation of only ~10%. This exaggerated sensitivity to shape will make it difficult to define representative angular scattering curves for many real-world nonspherical scattering problems which involve imperfect shape information.


Abnormal cardiac enzyme responses after strenuous exercise: alternative diagnostic aids.
Serial estimations of activities of creatine kinase and its MB isoenzyme, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase and of concentrations of alpha(1)-acid glycoprotein were performed in 15 healthy well-trained male marathon runners. Estimations were made initially within three days before a race and then one, 24, and 96 hours after the race. Technetium-99m pyrophosphate myocardial scintigraphy was carried out at the initial prerace assessment and repeated 48 to 96 hours after the race. None of the subjects developed cardiac symptoms during or after the race.Activities of creatine kinase and creatine kinase MB became maximal 24 hours after the race. One and 96 hours after the race two and five subjects, respectively, showed amounts of creatine kinase MB totalling 5% or more of total creatine kinase. Lactate dehydrogenase activity peaked at one hour after the race, and activities of aspartate and alanine aminotransferases peaked at 24 and 96 hours after the race, respectively. Activities of all these enzymes showed a significant increase from prerace values during the rest of the study. Electrocardiographic features noted were similar to those reported elsewhere in athletes under similar conditions. They included first-degree heart block, incomplete right bundle-branch block, left ventricular hypertrophy, pseudoischaemic T-wave changes, and early repolarisation of variant ST-segment elevations in precordial leads. Technetium-99m pyrophosphate myocardial scintigraphy did not show evidence of myocardial damage before or after the race. Alpha(1)-acid glycoprotein concentrations were normal throughout.These data suggest that reliance on standard enzyme estimations and electrocardiographic criteria may yield false-positive indicators of myocardial injury during prolonged strenuous exercise. Technetium-99m pyrophosphate scintigraphy and alpha(1)-acid glycoprotein measurements offer additional information and may usefully be employed in evaluating circulatory collapse associated with such exercise.


Goth migration induced changes in the matrilineal genetic structure of the central-east European population.
For years, the issues related to the origin of the Goths and their early migrations in the Iron Age have been a matter of hot debate among archaeologists. Unfortunately, the lack of new independent data has precluded the evaluation of the existing hypothesis. To overcome this problem, we initiated systematic studies of the populations inhabiting the contemporary territory of Poland during the Iron Age. Here, we present an analysis of mitochondrial DNA isolated from 27 individuals (collectively called the Mas-VBIA group) excavated from an Iron Age cemetery (dated to the 2nd-4th century A.D.) attributed to Goths and located near Masłomęcz, eastern Poland. We found that Mas-VBIA has similar genetic diversity to present-day Asian populations and higher diversity than that of contemporary Europeans. Our studies revealed close genetic links between the Mas-VBIA and two other Iron Age populations from the Jutland peninsula and from Kowalewko, located in western Poland. We disclosed the genetic connection between the Mas-VBIA and ancient Pontic-Caspian steppe groups. Similar connections were absent in the chronologically earlier Kowalewko and Jutland peninsula populations. The collected results seem to be consistent with the historical narrative that assumed that the Goths originated in southern Scandinavia; then, at least part of the Goth population moved south through the territory of contemporary Poland towards the Black Sea region, where they mixed with local populations and formed the Chernyakhov culture. Finally, a fraction of the Chernyakhov population returned to the southeast region of present-day Poland and established the archaeological formation called the "Masłomęcz group".


Acquired resistance to targeted therapies in advanced non-small cell lung cancer: new strategies and new agents.
Although the transition to molecularly defined patient subgroups in advanced non-small cell lung cancer (NSCLC) often leads to dramatic and prolonged responses to an inhibitor of an identified oncogenic mutation, acquired resistance eventually ensues. The optimal approach to management in that setting remains the subject of ongoing research, although it is possible to identify several points that distinguish it from traditional tenets based on conventional chemotherapy. Such patients are not equivalent to those who have progressed on first-line chemotherapy, and consideration of initiation of chemotherapy-based regimens as if the patient were being treated first line in the absence of an oncogenic mutation is a reasonable consideration. Acquired resistance is often partial; therefore, continued treatment with the same targeted therapy or another agent against the same target is a strategy favored by many experts, in part to minimize the risk of "rebound progression" that may occur when the targeted therapy is withdrawn. Progression within the central nervous system (CNS) may occur because of poor penetration of the systemic targeted therapy into the CNS, rather than true cellular resistance to the therapy itself; accordingly, local therapy for "brain only" progression with sustained targeted therapy for extracranial disease can be associated with prolonged disease control. Finally, patients with acquired resistance to a targeted therapy are ideal candidates for clinical trials when available, particularly when repeat biopsies of progressing lesions can help elucidate mechanisms of resistance and thereby lead to histologically and molecularly informed treatment decisions.


Mobilising elementary and secondary school students for tuberculosis case finding in Anhui, China.
To evaluate the implementation of a FIDELIS (Fund for Innovative DOTS Expansion through Local Initiatives to Stop TB) project in Anhui Province, China. A survey card was designed for students to identify individuals who might have tuberculosis (TB) in their family. Teachers provided health education on TB before distributing the survey cards. Survey cards identifying individuals with respiratory symptoms for ≥3 weeks were sent by the teachers to village doctors who were trained to visit symptomatic individuals and advise them to undergo sputum examination. Data were routinely collected in the implementation of the FIDELIS project, and quarterly reports from the National Tuberculosis Programme were analysed. The detection of new smear-positive TB cases before and after FIDELIS, as well as with and without FIDELIS, were compared. In the first year, a total of 2 387 405 students were involved and 23 079 symptomatic individuals were examined, among whom 2307 (10.3%) were diagnosed with smear-positive TB. Case detection in FIDELIS counties increased by a factor of 3.5 during the FIDELIS period compared with before FIDELIS, and that in non-FIDELIS counties by a factor of 3.1 (P = 0.001). It was feasible to massively mobilise students for TB case finding through collaboration between the health care and education systems.


Comparison of effectiveness of acupuncture therapy and conventional drug therapy on psychological profile of migraine patients.
Migraine is a painful condition in which patients suffer from recurrent episodes of disabling pain, which could be very severe and can lead to grave psychological disturbances. There is no curative treatment for migraine, but there are various treatment modalities, though, with conflicting reports on their efficacy. This study was conducted to compare the effectiveness of electro acupuncture therapy and the conventional drug therapy on the psychological profile of migraneurs based on the assessment of quality of life and disability parameters. Migraneurs (n = 60) were recruited from the Psychiatry and Neurology OPD, Guru Tegh Bahadur Hospital, Delhi. Following a written consent, migraneurs were randomly allocated into 2 study groups--Group A received 10 sittings of electro acupuncture on selected acupuncture points over a period of 30 days, while for the same duration the Group D received a conventional drug therapy in the form of oral flunarizine 20 mg OD along with paracetamol 500 mg SOS. The patients were assessed twice, before and after completion of the treatment programme (30 days). The quality of life was assessed with WHOQOL BREF (WHO Quality of Life Biomedical Research and Education Foundation) questionnaire and the disability was assessed with MIDAS (Migraine Disability Assessment) questionnaire. Statistical analysis was performed using repeated measure's ANOVA with Tukey's test. Migraneurs were found to have lower quality of life and higher disability scores but following the treatment regimes, the 2 study groups showed a significant improvement in both the parameters studied. It was however observed, that the acupuncture group showed a better response and was thus found to be more effective as compared to the drug group (P = 0.005 to 0.000). We thus conclude that acupuncture is a better treatment option than the conventional drug therapy in not only relieving the pain of migraine but in also improving the psychological profile in migraneurs. Hence its use should be encouraged as an alternative/adjunct treatment for migraine.


[Clinical efficacy of serum PIVKA-II in the diagnosis and follow up after treatment of hepatocellular carcinoma].
Protein induced by vitamin K absence or antagonist II (PIVKA-II) appears to be a useful tumor marker for the evaluation of patients with hepatocellular carcinoma (HCC). But the usefulness of PIVKA-II was not yet clear in Korea where hepatitis B-virus is endemic. We investigated the usefulness of PIVKA-II in the diagnosis and follow-up after treatment of HCC. We studied patients with HCC which was pathologically confirmed. PIVKA-II was measured by enzyme immunoassay. PIVKA- levels before and after treatment, in correlation with imaging studies, were analyzed for the comparison of treatment responses. Kappa index was obtained. A total of 129 patients were included. 93 patients (72%) were HBsAg positive. 86 patients (67%) were PIVKA-II >40 mAU/mL. 52 patients (40%) were AFP >20 ng/mL and 77 patients (60%) were AFP < or = 20 ng/mL. Of 77 patients, 40 patients (52%) showed PIVKA-II >40 mAU/mL. 68 of 129 patients were evaluated treatment response. On the basis of radiologic response, CR was 33, PR 17, SD 12, and PD 6. Of the 33 radiologic CR patients, 30 patients were CR and 3 patients were PR by means of PIVKA-II response. Of the 17 radiologic PR patients, 6 patients were CR and 7 patients were PR. Therefore, tumor responses by radiologic and PIVKA-II were well correlated (Kappa index was 0.59). PIVKA-II can be used as a useful tumor marker for patients with HCC, especially those with low levels of AFP, before and after treatment in Korea.


The unfolded protein response controls induction and activation of ADAM17/TACE by severe hypoxia and ER stress.
The family of ADAM (a disintegrin and metalloproteinase) proteins has been implicated in tumor initiation and progression. ADAM17/tumor necrosis factor-α (TNFα)-converting enzyme (TACE) has been initially recognized to release TNFα as well as its receptors (TNFRs) from the membrane. ADAM17, TNFα and TNFR have been found upregulated in cancer patients, although the underlying mechanisms remain largely unknown. As hypoxia is a hallmark of cancer that can lead to severe stress conditions accumulating in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), we investigated the role of these stress conditions in the regulation of ADAM17 and release of TNFR1.We found that severe hypoxia induced ADAM17 expression and activity. Although hypoxia-inducible factor 1α (HIF1α) was important to maintain basal ADAM17 mRNA levels during moderate hypoxia, it was not sufficient to induce ADAM17 levels under severe hypoxia. Instead, we found that ADAM17 induction by severe hypoxia can be mimicked by ER stressors such as Thapsigargin and occurs as a consequence of the activation of the PERK/eIF2α/ATF4 and activating transcription factor 6 (ATF6) arms of UPR in several tumor cell lines. ADAM17 expression was also increased in xenografts displaying ER stress because of treatment with the vascular endothelial growth factor (VEGF) inhibitory antibody Bevacizumab. Additionally, severe hypoxia and ER stress activated ADAM17 and ectodomain shedding of TNFR1 involving mitogen-activated protein (MAP) kinases and reactive oxygen species (ROS). Collectively, these results show that ADAM17 is a novel UPR-regulated gene in response to severe hypoxia and ER stress, which is actively involved in the release of TNFR1 under these conditions. These data provide a novel link between severe hypoxic stress conditions and inflammation in the tumor environment.


Mutations in the region encoding the central domain of helper component-proteinase (HC-Pro) eliminate potato virus X/potyviral synergism.
Coinfection of tobacco plants with potato virus X (PVX) and any of several members of the potyvirus group causes a synergistic disease characterized by a dramatic increase in symptom severity correlated with a 3- to 10-fold increase in the accumulation of PVX in the first systemically infected leaves. We have recently shown that PVX/potyviral synergistic disease is mediated by expression of potyviral 5'-proximal sequences encoding P1, helper component-proteinase (HC-Pro), and a fraction of P3 (termed P1/HC-Pro sequence). Here we report the effect of mutations in this potyviral sequence on the induction of synergistic disease. Three transgenic tobacco lines expressing the tobacco etch potyvirus (TEV) P1/HC-Pro sequence with mutations within the P1 coding region were not impaired in their ability to mediate synergism when infected with PVX. In contrast, two of three transgenic lines with mutations in the HC-Pro coding region were unable to induce the synergistic increases in either symptom severity or PVX accumulation. Loss of synergistic function was associated with mutations within the region encoding the central domain of HC-Pro, while the ability to induce synergism was retained in a transgenic line expressing HC-Pro with an alteration in the amino-terminal "zinc-finger domain." In coinoculation experiments, a TEV mutant lacking the sequence encoding the zinc-linger domain of HC-Pro induced a typical synergistic response in interaction with PVX. The results indicate that the zinc-finger domain comprising the first 66 amino acid residues of HC-Pro is dispensable for induction of synergistic disease and transactivation of PVX multiplication, while regions within the central domain of HC-Pro are essential for both of these responses.


Using multiparametric MRI to 'personalize' biopsy for men.
In recent years, multiparametric magnetic resonance imaging (mpMRI) of the prostate has shown promise as a modality to identify areas of suspicion within the gland which correlate with cancer location and disease extent. However, optimal individualization of prostate biopsy using mpMRI relies on aligning the relative benefits of MRI-targeted approaches with the goals of biopsy. For men with prior negative biopsies, mpMRI allows improved detection of occult high-grade cancers missed by repeat systematic biopsy but also has the potential to identify men who will not benefit from repeat biopsy due to a low likelihood of significant disease. For men with prior low-grade cancer diagnosis, the addition of MRI-targeted biopsy may identify those who are poor candidates for active surveillance by detecting high-risk disease without serial biopsies. For men without prior biopsy, mpMRI and targeted biopsy may help improve high-grade cancer diagnosis and significantly limit the detection of low-risk disease. mpMRI of the prostate is a promising tool to address many of the shortcomings of traditional systematic prostate biopsy. Biopsy history plays a critical role in determining how to assess the potential advantages and disadvantages of prostate mpMRI in the context of each patient. Although these benefits have been suggested by published clinical outcomes data, there is a need for prospective validation of mpMRI and MRI-targeted biopsy in comparison with the current approach of systematic biopsy for all men, to define new paradigms for prostate cancer detection and risk stratification.


Effect of rosuvastatin treatment on cholesterol efflux from human macrophages.
One of the positive effects of rosuvastatin is an increase in HDL cholesterol (HDL-C). An increase in HDL-C is considered as one of the positive effects of this type of statin, although it does not necessarily correspond to the actual reverse cholesterol transport (RCT) rate. We analyzed the influence of statin induced changes in HDL-C on cholesterol efflux (CHE), the key step affecting the RCT. Fourteen subjects (7 men, age: 50.9 ± 8.4 years and 7 women, age: 59.7 ± 10.6 years) with mixed dyslipidemia received 20 mg of rosuvastatin daily for 3 months. Before the initiation of statin therapy and at the end of the study period, the CHE from 14C cholesterol-labeled macrophages was determined in addition to parameters related to lipid metabolism. CHE was calculated as the percentage of radioactivity released from the macrophages into the media containing 5% of the examined plasma. The rosuvastatin administration resulted in significant reductions of total cholesterol, LDL cholesterol, and apolipoprotein B and a significant increase in HDL-C (from 1.43 mmol/l to 1.52 mmol/l, p=0.05), while the levels of apolipoprotein A1 remained unchanged. There was no significant increase in CHE (from 16.1% to 17.6%, p for trend = 0.053). Individual changes in HDL-C correlated significantly (p<0.05) with individual changes of CHE (r=0.76). Administration of rosuvastatin increases HDL-C, and individual changes correlate with the individual increases of CHE from macrophages.


How do we see art: an eye-tracker study.
We describe the pattern of fixations of subjects looking at figurative and abstract paintings from different artists (Molina, Mondrian, Rembrandt, della Francesca) and at modified versions in which different aspects of these art pieces were altered with simple digital manipulations. We show that the fixations of the subjects followed some general common principles (e.g., being attracted to saliency regions) but with a large variability for the figurative paintings, according to the subject's personal appreciation and knowledge. In particular, we found different gazing patterns depending on whether the subject saw the original or the modified version of the painting first. We conclude that the study of gazing patterns obtained by using the eye-tracker technology gives a useful approach to quantify how subjects observe art.


Sexual Dimorphism in Digit Ratios Derived from Dorsal Digit Length among Adults and Children.
Sexual dimorphism in ventrally measured digit ratios (2D:4D and other) has been related to prenatal sex-hormone levels. In the present series of three studies, we measured all digit lengths (excluding the thumb) on the dorsal, rather than the ventral, side of left and right hands and investigated the sexual dimorphism in digit ratios in three independent samples, two of them comprising adults (Study I, N = 104; Study II, N = 154), and one further, comprising kindergarten children (Study III, N = 64). Results show that men have lower digit-ratio values compared to women in digit ratios that include digit 5 as one of the constituents of the ratio (i.e., the 4D:5D, 3D:5D, and 2D:5D ratios). Boys have lower values compared to girls for the 4D:5D and 3D:5D ratios, and there is a similar trend of sexual dimorphism in the 2D:5D ratio. Thus, based on the evidence from dorsally measured digit ratios, the present findings from three samples are consistent with the idea that early sex-hormonal effects might be stronger for digit ratios involving digit 5, as compared to the classic, and frequently studied, ventrally measured 2D:4D ratio.


Volitional control of single-electrode high gamma local field potentials by people with paralysis.
Intracortical brain-computer interfaces (BCIs) can enable individuals to control effectors, such as a computer cursor, by directly decoding the user's movement intentions from action potentials and local field potentials (LFPs) recorded within the motor cortex. However, the accuracy and complexity of effector control achieved with such "biomimetic" BCIs will depend on the degree to which the intended movements used to elicit control modulate the neural activity. In particular, channels that do not record distinguishable action potentials and only record LFP modulations may be of limited use for BCI control. In contrast, a biofeedback approach may surpass these limitations by letting the participants generate new control signals and learn strategies that improve the volitional control of signals used for effector control. Here, we show that, by using a biofeedback paradigm, three individuals with tetraplegia achieved volitional control of gamma LFPs (40-400 Hz) recorded by a single microelectrode implanted in the precentral gyrus. Control was improved over a pair of consecutive sessions up to 3 days apart. In all but one session, the channel used to achieve control lacked distinguishable action potentials. Our results indicate that biofeedback LFP-based BCIs may potentially contribute to the neural modulation necessary to obtain reliable and useful control of effectors. NEW & NOTEWORTHY Our study demonstrates that people with tetraplegia can volitionally control individual high-gamma local-field potential (LFP) channels recorded from the motor cortex, and that this control can be improved using biofeedback. Motor cortical LFP signals are thought to be both informative and stable intracortical signals and, thus, of importance for future brain-computer interfaces.


High-performance liquid chromatographic separation of the enantiomers of organophosphorus pesticides on polysaccharide chiral stationary phases.
High-performance liquid chromatographic separation of the individual enantiomers of 12 organophosphorus pesticides (OPs) was obtained on polysaccharide enantioselective HPLC columns using alkane-alcohol mobile phase. The OP pesticides were crotoxyphos, dialifor, fonofos, fenamiphos, fensulfothion, isofenphos, malathion, methamidophos, profenofos, crufomate, prothiophos and trichloronate. The enantiomers of fenamiphos, fensulfothion, profenofos and crufomate were separated on CHIRALPAK AD; the enantiomers of fenamiphos were also separated on CHIRALPAK AS; the enantiomers of methamidophos, crufomate and trichloronate were separated on CHIRALCEL OD; the enantiomers of crotoxyphos, dialifor, fonofos, malathion, prothiophos and trichloronate were separated on CHIRALCEL OJ; and the enantiomers of isofenphos were separated on CHIRALCEL OG. Baseline or partial separation of the enantiomers of six of these OP pesticides was obtained on CHIRALCEL OJ. In continued method development, the separation of the enantiomers of the 12 OPs was investigated more extensively on CHIRALCEL OJ to determine whether the mobile phase composition, flow-rate and column temperature could be optimized to yield at least partial separation of the enantiomers. Chromatographic conditions were found that gave either baseline or near baseline separations of the enantiomers of the 12 OPs on the CHIRALCEL OJ column.


Role of soybean mosaic virus-encoded proteins in seed and aphid transmission in soybean.
Soybean mosaic virus (SMV) is seed and aphid transmitted and can cause significant reductions in yield and seed quality in soybean (Glycine max). The roles in seed and aphid transmission of selected SMV-encoded proteins were investigated by constructing mutants in and chimeric recombinants between SMV 413 (efficiently aphid and seed transmitted) and an isolate of SMV G2 (not aphid or seed transmitted). As previously reported, the DAG amino acid sequence motif near the amino terminus of the coat protein (CP) was the major determinant in differences in aphid transmissibility of the two SMV isolates, and helper component proteinase (HC-Pro) played a secondary role. Seed transmission of SMV was influenced by P1, HC-Pro, and CP. Replacement of the P1 coding region of SMV 413 with that of SMV G2 significantly enhanced seed transmissibility of SMV 413. Substitution in SMV 413 of the two amino acids that varied in the CPs of the two isolates with those from SMV G2, G to D in the DAG motif and Q to P near the carboxyl terminus, significantly reduced seed transmission. The Q-to-P substitution in SMV 413 also abolished virus-induced seed-coat mottling in plant introduction 68671. This is the first report associating P1, CP, and the DAG motif with seed transmission of a potyvirus and suggests that HC-Pro interactions with CP are important for multiple functions in the virus infection cycle.